The Simpson-Golabi-Behmel syndrome (SGBS) is a human disorder associated with both pre- and postnatal overgrowth, and a complex assortment of congenital defects including skeletal abnormalities. Mutations in the gene encoding the heparan sulfate proteoglycan glypican-3 (GPC3) cause this disorder, but the mechanisms by which these phenotypic traits arise is unknown. The investigators long-term objective is to understand the molecular details of how loss of GPC3 function causes these complex traits and they have chosen to focus as short term objective on understanding the molecular details of how loss of GPC function causes these complex traits and they have chosen to focus as short term objective on understanding the biology of a specific feature of the SGBS phenotype, skeletal overgrowth and malformation. David Ornitz's lab has determined that the fibroblast growth factor receptor-3 (Fgfr3) plays a critical role in the essential regulation of bone development. Signaling through this receptor has an essential requirement for a heparan sulfate containing proteoglycan that functions as a co-receptor; however, the specific heparan sulfate proteoglycan that functions as a co-receptor; however, the specific heparan sulfate proteoglycan that functions as a co-receptor; however, the specific heparan sulfate proteoglycan that functions as a co-receptor; however, the specific heparan sulfate proteoglycan that serves this function has not been identified. The investigators have found that Gpc3 and Fgfr3 are co-expressed in bone, and, since loss-of-function mutations of both Gpoc3 and Fgfr3 are associated with skeletal overgrowth and malformation, they have hypothesized that Gpc3 may be the co-receptor required for FGFR3 signaling. Only Gpc6, a new member of this gene family recently discovered in this laboratory, has similar expression in bone. The studies proposed here would make use of existing mouse mutants for Gpc3 function of glypicans in bone growth and differentiation. These will include studies designed to: (I) test the hypothesis tat GPC3 is a co-receptor for FGFR3 by molecular genetic techniques, (ii) evaluate the hypothesis that GPC3 and GPC6 by molecular genetic techniques, (ii) evaluate the hypothesis that GPC3 and GPC6 have distinct functions in bone growth and differentiation through the creation and evaluation of Gpc6 mutants, (iii) explore the molecular mechanisms of glypican functions in bone by examining gene expression profiles associated with null mutations of Gpc3 and/or Gpc6, and (iv) carry out a phenotypic-genotypic analysis of human patients with SGBS in an attempt to identify unique Gpc3 mutations associated with organ specific developmental malformations. This approach will provide new insights into the role of glypicans in the pathogenesis of SGBS and lead to novel clinical approaches for the diagnosis and treatment of affected children.